Cardiovascular diseases represent the worldwide leading cause of mortality and coronary disease is responsible by itself for more than half of these deaths. The onset of a coronary event is due, in the vast majority of cases, to the disruption of a vulnerable coronary atheroma plaque. Coronagraphy, a present standard technique for diagnosing the coronary disease, does not allow identification of non-stenosing plaques.
Nuclear imaging obviously has significant advantages for molecular imaging of the vulnerable atheroma plaque. Many tracers, of diverse chemical natures, among which lipoproteins, peptides, oligopeptides, antibodies, sugars, antisense nucleotides and nanoparticles, have been evaluated experimentally for molecular imaging (Riou et al. (2009) Curr. Med. Chem. 16:1499-1511). The main evaluated targets have been oxidized LDLs and their receptors, the inflammatory phenomenon via cell imaging of macrophages, or imaging of receptors of enzymes expressed by this cell type, the apoptotic phenomenon and the neo-angiogenic phenomenon. Among the tracers targeting the inflammatory process, 99mTc-MCP-1 for nuclear imaging in the SPECT (Single Photon Emission Computed Tomography) mode and [18F]-FDG for the PET (Positron Emission Tomography) method have allowed non-invasive in vivo imaging of the accumulation of macrophages in experimental atherosclerotic lesions. On a clinical level, [18F]-FDG and 99mTc-Annexin A5 have allowed non-invasive imaging of the accumulation of macrophages and of apoptotic cells, respectively in carotidian atheroma plaques of symptomatic patients. However, none of these radiotracers are presently used in clinical practice systematically, mainly because of their incapacity of attaining sufficient lesions-to-background-noise ratios at coronary lesions. Indeed, nuclear imaging of the vulnerable plaques at the coronary arteries is particularly difficult because of the small volume of the lesions and of their proximity with the blood which contains an unbound circulating tracer. Therefore, no clinical test exists at the present time showing the feasibility of imaging of coronary atheroma.
VCAM-1 is a glycoprotein from the family of immunoglobulins, the expression of which is induced in a pro-atherogenic condition. Its expression is restricted to the areas of development of atheroma plaques and it lasts during the totality of the development of the vulnerable plaque. The role of VCAM-1 is to ensure the recruitment of inflammation cells (lymphocytes and monocytes) towards the plaque. The expression of VCAM-1 is therefore directly correlated with the accumulation of macrophages, which is recognized as one of the major criteria in the definition of a vulnerable plaque (Naghavi et al. (2003) Circulation 108:1772-1178). The present inventors have previously developed radiotracers containing a peptide sequence capable of binding to VCAM-1. They have shown on an atherosclerotic rabbit model that the binding of this radiotracer on autoradiographic images ex vivo was correlated with the areas of development of atheroma plaques and with the expression of VCAM-1 (Broisat et al. (2007) Eur. J. Nucl. Med. Mol. Imaging 34:830-840). However, because of the circulating blood activity of this tracer, it is not possible to use it in vivo in medical imaging.
Indeed, in a general way, the signal to noise ratio should be high in order to produce quality medical imaging. An ideal radiotracer is therefore characterised by high affinity and specificity for its target, good solubility and stability, efficient radiolabeling, a small size as well as by rapid removal from the blood, so that images with a high contrast level may be rapidly obtained after administration of the tracer. This is most particularly crucial in the case of the atheroma plaque because of its small size and of its intravascular localisation.